Toxicokinetics Of Alpha-Thujone Following Intravenous And Gavage Administration Of Alpha-Thujone Or Alpha- And Beta-Thujone Mixture In Male And Female F344/N Rats And B6c3f1 Mice

Plants containing thujone have widespread use and hence have significant human exposure. alpha-Thujone caused seizures in rodents following gavage administration. We investigated the toxicokinetics of alpha-thujone in male and female F344/N rats and B6C3F1 mice following intravenous and gavage administration of alpha-thujone or a mixture of alpha- and beta-thujone (which will be referred to as alpha,beta-thujone). Absorption of alpha-thujone following gavage administration was rapid without any dose-, species-, sex- or test article-related effect. Absolute bioavailability of alpha-thujone following administration of alpha-thujone or alpha,beta-thujone was generally higher in rats than in mice. In rats, females had higher bioavailability than males following administration of either test article although a sex difference was not observed in mice. C-max and AUC(infinity) increased greater than proportional to the dose in female rats following administration of alpha-thujone and in male and female mice following administration of alpha,beta-thujone suggesting possible saturation of elimination kinetics with increasing dose. Dose-adjusted AUC(infinity) for male and female rats was 5- to 15-fold and 3- to 24-fold higher than mice counterparts following administration of a-thujone and alpha,beta-thujone, respectively (p-value < 0.0001 for all comparisons). Following both intravenous and gavage administration, et-thujone was distributed to the brains of rats and mice with females, in general, having higher brain:plasma ratios than males. These data are in support of the observed toxicity of alpha-thujone and alpha,beta-thujone where females were more sensitive than males of both species to alpha-thujone-induced neurotoxicity. In general there was no difference in toxicokinetics between test articles when normalized to alpha-thujone concentration. Published by Elsevier Inc.